It is now widely appreciated that cancer is a genetic disease. Much of the understanding of the important genetic factors in this disease process have come from the analysis of chromosomal alterations and genetic changes in tumors and transformed cells, the identification of familial clusters of cancer and the identification, through molecular cloning, of the disease genes. The identification of the genes which are playing a casual role in cancer is an important entry point into eventually defining individuals who are "at risk", and using knowledge of the genes and their function to modify the disease process/improve prognostic outcomes. Breast cancer, a highly prevalent disease in women, is known to run in families. Germ line mutations in several different genes such p53, the androgen receptor and brcal have been shown to confer a high risk of disease. Linkage has recently been recognized for a susceptibility locus on human chromosome 13q (Brca2), there are likely to be other genes involved in breast cancer which can not be readily identified by linkage because of issues such as the high background of the disease. There are two objectives in this research proposal. First, they will generate mouse models which mimic the genetic deficiency observed in humans, initially for Brcal and subsequently for Brca2. Second, they will attempt to identify tumor suppressor genes which are involved in breast cancer using a novel genetic screen in vivo. They have developed a technology which allows them to specifically delete large regions of the mouse genome selected on the basis of synteny with human chromosomal regions that have been observed to undergo loss of heterozygosity in breast tumors. Mice with deletions will be infected with Mouse Mammary Tumor Virus (MMTV) which can insertionally inactivate the single tumor suppressor allele on the non-deleted chromosome. This facilitates the clonal expansion of the mutated cell and the subsequent molecular identification of the insertionally inactivated tumor suppressor gene.